10,10-Disubstituted-2,3,4,10-tetrahydro-and 1,2,3,4,10a-hexahydropyrimidol {8 1,2-a{9 indole derivatives

ABSTRACT

A group of heterocyclic compounds useful as anti-depressant agents is described. The compounds may also be used as antiinflammatory agents, anti-histamine agents, diuretics and hypoglycaemics. The compounds are 2,3,4,10-tetrahydropyrimido(1,2-a)indoles and 1,2,3,4,10, 10a-hexahydropyrimido(1,2a)indoles substituted in the 10-position by a hydroxy or lower acyloxy residue together with a phenyl, substituted phenyl, lower alkyl, lower alkynyl, benzyl, naphthyl, thienyl or pyridyl residue. The compounds are optionally substituted in the 2,3,4,6,7,8, or 9 positions and the Hexahydropyrimido(1,2-a) indoles may also be substituted in the 1-position. Exemplary of the compounds of the invention is 10-(m-chlorophenyl)-2,3,4,10tetrahydropyrimido(1,2-a)indol-10-ol.

United States Patent [1 1 White 1 June 24, 1975l0,l0-DISUBSTlTUTED-2,3,4,l0-

TETRAHYDRO-AND 1,2,3,4,l0A-HEXAHYDROPYRIMIDOL [1,2-A]INDOLE DERIVATIVES[75] Inventor: Alan Chapman White, Windsor,

England [73] Assignee: John Wyeth and Brother (Ltd.),

Maidenhead, England [22] Filed: May 18, 1973 [21] Appl. No.: 361,701

Related US. Application Data [63] Continuation-impart of Ser. No.211,105, Dec. 22,

1971, abandoned.

[30] Foreign Application Priority Data Jan, 11, 1971 UnitedKingdom1250/71 Sept. 2, 1971 United Kingdom 40959/71 [52] US. CL. 260/251 A;260/256.4 Q [51] Int. Cl C07d 51/46 [58] Field of Search 260/251 A,256.4 Q

[56] References Cited OTHER PUBLICATIONS White et al. CA. 77, 126681 f(1972). Portnov et al. CA. 77, 48377 v (1972).

Primary Examiner-Donald G. Daus Assistant Examiner- -Raymond V. Rush [57] ABSTRACT A group of heterocyclic compounds useful as antidepressantagents is described. The compounds may also be used as anti-inflammatoryagents, antihistamine agents, diuretics and hypoglycaemics. Thecompounds are 2,3,4, 1 0-tetrahydro-pyrimido[ 1,2- a]indoles andl,2,3,4,l0, l0a-hexahydropyrimido[1,2- a]indoles substituted in thelO-position by a hydroxy or lower acyloxy residue together with aphenyl, substituted phenyl, lower alkyl, lower alkynyl, benzyl,naphthyl, thienyl or pyridyl residue. The compounds are optionallysubstituted in the 2,3,4,6,7,8, or 9 positions and theHexahydropyrimido[l,2-a] indoles may also be substituted in thel-position. Exemplary of the compounds of the invention isl0-(rn-chlorophenyl)- 2,3 ,4, l 0-tetrahydropyrimido[ l ,2-a]indol- 10-01.

12 Claims, No Drawings 1 110,10-DISUBSTITUTED-2,3,4,10-TETRAHYDRO- ANDll,2,3,4,IG-A-HEXAHYDROPYRIMIDOL [1,2-A]INDOLE DERIVATIVES Thisapplication is a continuation-in-part of copending application Ser. No.211,105 filed Dec; 22,1971 by Alan C. White now abandoned. The inventionrelates to a novel series of pyrimido[1,2-a]indole derivatives, to aprocess for their preparation and to pharmaceutical compositionscontaining them.

The compounds of the present invention are indole derivatives having thegeneral formula (I) the acid addition salts thereof withpharmaceutically acceptable acids and the quaternary ammonium saltsthereof, in which R represents a hydroxy or lower acyloxy group, Rrepresents a member of the group consisting of phenyl, lower alkyl,lower alkynl, benzyl, naphthyl, thienyl, pyridyl and phenyl substitutedby at least one halogen, trifluoromethyl, lower alkly or lower alkoxygroup, R and R (which may be the same or different) represent hydrogen,halogen or lower alkoxy, R and R (which may be the same or different)represent hydrogen or lower alkyl, the dotted line represents anoptional bond in the position indicated, and R, which is present onlywhen the optional bond represented by the dotted line is absent,represents hydrogen or lower alkyl.

The term "lower as used herein means the radical contains up to 6,preferably up to 4 carbon atoms. It is to be understood that R and R maybe on the same or different carbon atoms, but preferably they are bothon the same carbon atom e.g., at position 3 in the tetrahydroandhexahydropyrimido[ l,2-a]indoles.

Since the compounds of the invention may possess one or more asymmetriccarbon atoms, optical enantiomorphs are possible and the compounds ofthe invention may be the pure enantiomorphs or mixtures of suchenantiomorphs, such as the racemates.

Examples of radicals R are hydroxyl, acetoxy, propionoxy and butyryloxy.Preferred examples of radicals R are phenyl, naphthyl, fury], thienyl,pyridyl and phenyl substituted by halogen (for example fluorine,chlorine or bromine), lower alkyl (for example methyl, ethyl, propyl, orbutyl), lower alkoxy (for example methoxy, ethoxy, propoxy or butoxy)and trifluoromethyl. The radical R may also be a lower alkyl radical,for example methyl, ethyl, propyl or butyl, or a lower alkynyl radical,which may be straight or branched chain, and which may for example beethynyl or propargyl. The following are examples of R and R hydrogen,lower alkoxy (e.g., methoxy, ethoxy, propoxy and butoxy), and halogene.g., chlorine and bromine). Examples of R and R are hydrogen and loweralkyl groups such as methyl, ethyl, propyl and butyl.

The R radicals may be hydrogen or straight or branched chain lower alkylradicals, e.g., methyl, ethyl, propyl and butyl.

A preferred class of compounds of formula (I) are thetetrahydropyrimido[l,2-a]indoles of general formula (la) or acidaddition salts thereof with pharmaceutically acceptable acids or thequaternary ammonium salts thereof, wherein R, R, R and R have themeanings given above in connection with formula (I). Compounds ofparticular value are those in which R R, R and R represent hydrogenatoms, R represents hydroxyl and R represents phenyl or phenylsubstituted by at least one halogen, trifluoromethyl, lower alkyl orlower alkoxy group. The ring system of the pyrimido[ l,2-a]indoles isnumbered as shown in general formula Ia.

Especially valuable compounds of formula (la) are: 2,3,4, 1O-tetrahydrol 0-phenylpyrimido[ l,2-a]indol- 10-01,

10-( m-chlorophenyl)-2,3 ,4,10-tetrahydropyrimido[ l,2-a]indol-1OIO-(p-chlorophenyl )-2,3,4, 1 O-tetrahydropyrimido[ l ,2-a]indol- 10-01,

2,3,4, 1 0tetrahydrol0-( 2-thienyl )pyrimido[ l ,2- a]indol-l0-ol, i

l0-( m-fluorophenyl )-2,3 ,4,10-

tetrahydropyrimido[ 1 ,2-a]indol- 1 0-01,10-(3,4-dichlorophenyl)-2,3,5,lO-

tetrahydropyrimido[ l,2-a]indol-l O-ol,lO-(m-chlorophenyl)-2,3,4,lO-tetrzihydro-3,3dimethylpyrimido[1,2-a]indol-lO-ol, 2,3 ,4, l O-tetrahydrolO-phenyl-3 ,3-

dimethylpyrimido[ l ,2-a]indol- 1 0-01, l O-(m-chlorophenyl )-2,3 ,4, lO-tetrahydropyrimido[ l ,2-a]indol- 1 0-01 and lO-( m-chlorophenyl )-2,3,4, l O-tetrahydropyrimido[ 1 ,2-a]indol- 1 0-01. Another class ofcompounds within formula (I) are the hexahydropyrimido[ l ,2-a]indoles,i.e., compounds of the general formula (lb) and the acid addition saltsthereof with pharmaceutically acceptable acids and the quaternaryammonium salts thereof wherein R, R, R R, R, R and R have the meaningsgiven above in connection with formula The tetrahydropyrimido[ l,2-a]indoles of general formula (Ia), can be prepared by a process whichcomprises reacting a ketone of general formula (II) R (II) N R Q (whereR R, R and R have the meanings given above) with an organometalliccompound known in the art for conversion of a ketone function to thegroup wherein R R, R and R are as defined in connection with formula (I)and R and R are taken together and represent an alkylene ketal or twolower alkoxy groups. The compounds of general formula (V) may beprepared by hydrogenating an appropriate N-substituted isatinderivative, for example, that of general formula (Ill) or dehydrating acorresponding amine, e.g., of the general formula (IV) where R, R, R, RR and R are as defined above.

The organometallic compound which is reacted with the ketone of generalformula (II) is preferably chosen from (a) Grignard reagents of formulaRMgY wherein Y is a halogen and R has the meanings defined above,

and (B) alkali-metal comgu .nids such as the lithium derivatives offormula RLi (particularly the aryl lithiums, for example phenyllithium). and sodium and potassium acetylide. The reaction of the ketoneof general formula (II) with the organometallic compound is generallycarried out in an inert organic solvent, for example ether ortetrahydrofuran, using the standard conditions known for the particularreaction concerned.

As already mentioned, if desired the compound in which R represents ahydroxy group and the dotted line represents a bond in the positionindicated may be lower acylated to introduce a lower acyloxy residue R.Such an acylation reaction is carried out by standard methods known inthe art. For example, the hydroxy compound may be treated with an acylchloride or acid anhydride, optionally in the presence of pyridine orother base.

The compounds of general formula (I) in which the bond represented bythe dotted line is absent (which have the general formula lb) can beprepared by reducing, a compound of general formula (Ia) or a quaternaryammonium salt thereof in which the cation has the formula a (VI) whereinR, R, R R, R and R have the meanings given above and R is a lower alkylgroup, and if desired converting a free base into an acid addition orquaternary ammonium salt thereof.

For example, when it is desired to prepare a compound of general formula(lb) in which R represents hydrogen, a compound of general formula (Ia)may be reduced by methods known in the art. Preferably the reduction iseffected by means of a hydride transfer reagent, particularly a complexmetal hydride such as sodium borohydride or lithium aluminum hydride.The reaction is conducted using the standard conditions known for theparticular reducing agent concerned.

When it is desired to prepare a compound of general formula (lb) inwhich R is lower alkyl, a quaternary compound in which the cation hasthe general formula (VI) is reduced as described above.

Once a compound of general formula (I) has been prepared in which R, R,R R, R, R and R have the meanings defined in connection with formula(I), one group R and/or R and/or R and/or R and/or R and- /or R (ifpresent) may, if desired, be converted into another group R and/or Rand/or R and/or R and/or R and/or R and/or R each within the abovedefined meanings of R, R, R R", R, R and R. For example, when R and/or Ris a hydrogen atom, this may be converted into a halogen group,particularly at the 8- position, by known methods, e.g., by treatmentwith N- chlorosuccinimide. When R is an alkynyl radical, this may bereduced to a lower alkyl radical R. If desired a hydroxyl function R atthe lO-position may be lower acylated to form a lower acyloxy residue Rby the methods described hereinbefore.

When R is a hydrogen atom, the compound may be alkylated by knownmethods to introduce a lower alkyl group R If necessary, any reactivegroup in a compound may be protected by known methods before performingany of the above reactions and the protectin'ggroup then removed byknown methods subsequent to the reaction.

The hydrolysis of the compounds of general formula (V) may be carriedout by methods known per se, for example, by heating with acid, e.g.dilute mineral acid such as hydrochloric acid. The yields of ketone(II), which may be isolated as its mineral acid salt by this method, isin the region of 50%. A preferred method for the hydrolysis consists intreating the compound with concentrated sulphuric acid at roomtemperature and isolating the compound as its free base (in yields ofthe order of 90%).

In a preferred method for preparing the compounds of formula (V), whichcan be hydrolysed to the starting ketones of formula (II), a substitutedisatin of general formula (Ill) is hydrogenated. The hydrogenation isusually carried out in the presence of a nickel, palladium or platinumcatalyst and at elevated temperatures and pressures. The use oftemperatures in the region of 100C usually gives rise to the tricycliccompound directly. In some instances and also when using somewhat lowertemperatures, the product isolated consists of a mixture of the desiredtricyclic compound and an intermediate amine of formula (IV) -CH C }Z.CHNH R (Iv) 7 a) .The amine of formula (IV) may be dehydrated to obtainthe desired tricyclic compound of formula (V) by subjecting the mixtureto azeotropic distillation with a solvent such as benzene, xylene ortoluene.

The N-substituted isatin derivatives such as those of formula (III) areknown in the literature or may be prepared by methods known forpreparing analogous compounds. For example, by reacting an isatin(bearing the substituents R and R in the aromatic ring) with aketalising agent, to ketalise one of the oxo groups and with analkylating agent, such as acrylonitrile or 3- bromopropionitrile tointroduce the appropriate group on the N-atom.

The compounds of formula (I) are capable of forming acid addition saltswith acids, particularly pharmaceutically acceptable acids, and theinvention also provides such salts. The salts may be isolated directlyfrom the processes described above or prepared by dissolving thespecific compound of formula (I) as its base in a suitable organicsolvent, and treating it with a solution of the selected acid, inaccordance with conventional procedures for preparing acid additionsalts from base compounds generally. As examples of acids, there may beused any of hydrochloric, hydrobromic, tar taric, phosphoric, maleic,citric, acetic or benzoic acid.

The compounds of general formula (I) are also capable of formingquaternary ammonium salts, and the invention also provides such salts.The quaternary salts may be prepared by treating the compound as itsbase in the presence or absence of a solvent, with an aryllower alkylhalide, lower alkyl halide, alkenyl halide, alkynyl halide or aminoloweralkyl halide. Examples of such halides are methyl iodide and benzylchloride and benzyl bromide.

The optical isomers of the compounds of formula (I) may be prepared byseveral processes. Preferably, a racemic mixture of a compound of thegeneral formula (I) is resolved by standard methods described in theliterature. The racemate may be prepared by any of the processesoutlined above. It is to be understood that the resolution may becarried out on the racemic mixture of the final desired product, or itmay be carried out on a racemate of one compound of general formula (I)and then the optical isomers subjected to afterprocesses (suchasalkylation, acylation, hydrolysis, hydrogenolysis, and reduction) togive the desired prod uct of formula (I).

Alternatively, an optically active isomer of a compound of the generalformula (I) can be prepared by any of the methods outlined aboveemploying an optically active starting material, or a resolution iscarried out at any stage prior to formation of the compound of generalformula (I). If necessary, the optically active isomer thus formed maybe subjected to such reactions as alkylation, acylation, hydrolysis,hydrogenolysis, and reduction, to give the desired product.

A resolution is preferably carried out on a racemic mixture of a basiccompound of general formula (I) by methods described in the literature,such as by use of an optically active acid. For instance, a solution ofthe racemate in a suitable solvent such as an alcohol is treated with asolution of an optically active acid to cause crystallisation of thesalt of one particular enantiomorph. The other enantiomorph can often beobtained from the mother liquors, or if necessary by treatment with abase and then with the other optical isomer of the optically activeacid, or alternatively a fresh solution of the racemate can be treatedwith a solution of the other enantiomorph of the optically active acid.The actual solvent and optically active acid to be used in any oneinstance cannot be predicted, and the choice is determinedexperimentally. The best combination is that which allows the salt to bemost easily isolated in a high state of purity (i.e., freedom from theother enantiomer) and in a crystalline form.

It has been found that D() and L(+)-tertaric acid are particularlysuitable for the resolution of some compounds of formula (I).

The compounds of the invention exhibit pharmacological activity asanti-depressants. In one method of evaluating their anti-depressantproperties the effect of the compounds on hypothermia in mice induced byreserpine is measured by the procedure of B. M. Askew, Lift Sciences(1963), 1, 725-730. The compounds are orally administered in a dosagerange of about 2 to about 50 mg/kg. to mice previously dosedsubcutaneously with 2 mg/kg of reserpine and the rise in rectaltemperature of the mice compared to that in a control group of animals.The following table illustrates the re- Rise in rectal temperature (C).

Dose (mg/kg p.o.)

Compound of Example l0-( m-Chlorophenyl )-2,3 ,4, l O-tetrahydropyrimido[l,2-a]indol-lO-ol is of particular interest since it shows many of theanti-depressant properties of conventional tricyclic anti-depressantsbut reduced anticholinergic side effects on pharmacological testing.

The compounds have also been assessed for anti inflammatory activity bytheir ability to inhibit experimentally-induced edema in the hind paw ofrats according to the procedure of Winter et al., Proc. Soc. Exp. Biol.and Med., (1962), 111, 544 and Buttle et al., Nature (1957), 179,629.The compounds were administered orally in a dose range of about 1 toabout 100 mg/kg and the percentage inhibition of the swelling of the pawas compared to control animals was measured. The following tableillustrates the results obtained with compounds which are particularlyactive in this test.

-Continued Compound of Dose (7L Inhibition Example (mg/kg p.o.)

I6 50 50 I7 50 63 I9 I 37 IO 37 20 30 32 2I l 46 5O 50 22 l 35 IO 35 23I00 61 24 IO 32 30 IO 38 45 IO 25 The compounds of the invention alsopossess some antihistaminic, diuretic and hypoglycemic activity whentested by standard pharmaceutical procedures.

In addition, lO-(p-chlorophenyl )-2,3,4, 10- tetrahydropyrimido[l,2-a]indol- 1 0-01 has anti-gastric ulcer activity as determined by aprocedure similar to that of Brodie and Hanson, J. Appl. Physiol, I960,15, 291-294. In this test the compound was found to produce over 60%inhibition of ulceration in rats when administered orally at a dose of10 or 30 mg./kg. The compound also demonstrated an inhibitory effectagainst the secretion of gastric juice when tested by the procedure ofShay et al., Gastroenterology, 1954, 26, 906 to 913. It showedsignificant decrease in the volume of gastric contents, theconcentration of acid and the amount of free and total acid whenadministered at a dose of 30 mg./kg. into the rat duodenum.

Depression in mammals may be treated by administering a pharmaceuticallyeffective amount of the indole derivatives of general formula (I) or anacid addition or quaternary ammonium salt thereof.

As the compounds of general formula (I) show pharmaceutical activity,the invention further provides a pharmaceutical composition whichcomprises a compound provided by the invention which may be micronised,in association with a pharmaceutically acceptable carrier. Any suitablecarrier known in the art can be used to prepare the pharmaceuticalcompositions. In such a composition, the carrier may be a solid, liquidor mixture of a solid and a liquid. Solid form compositions includepowders, tablets and capsules. A solid carrier can be one or moresubstances which may also act as flavouring agents, lubricants,solubilisers, suspending agent, binders, or tablet-disintegratingagents; it can also be an encapsulating material. In powders the carrieris a finely divided solid which is in admixture with the finely dividedactive ingredient. In tablets the active ingredient is mixed with acarrier having the necessary binding properties in suitable proportionsand compacted in the shape and size desired. The powders and tabletspreferably contain from 5 to 99, preferably 10-80% of the activeingredient. Suitable solid carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch gelatin,tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a lowmelting wax, and cocoa butter. The term composition is intended toinclude the formulation of an active ingredient with encapsulatingmaterial as carrier to give a capsule in which the active ingredient(with or without other carriers) is surrounded by carrier, which is thusin association with it. Similarly cachets are included.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable sterile liquid carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably a liquid carrier is one suitable for parenteral injection.Where the active ingredient is sufficiently soluble it can be dissolvedinnormal saline as a carrier; if it is too insoluble for this it canoften be dissolved in a suitable organic solvent, for instance aqueouspropylene glycol or polyethylene glycol solutions. Aqueous propyleneglycol containing from 10 to 75% of the glycol by weight is generallysuitable. In other instances compositions can be made by dispersing thefinely-divided active ingredient in aqueous starch or sodiumcarboxymethyl cellulose solution, or in a suitable oil, for instancearachis oil. Liquid pharmaceutical compositions which are sterilesolutions or suspensions can be utilised by intramuscular,interaperitoneal or subcutaneous injection. In many instances a compoundis orally active and can be administered orally either in liquid orsolid compositions.

Preferably the pharmaceutical composition is in unit dosage form. Insuch form, the composition is subdivided in unit doses containingappropriate quantities of the active ingredient; the unit dosage formcan be a packaged composition, the package containing specificquantities of compositions, for example packeted powders or vials orampoules. The unit dosage form can be a capsule, cachet or tabletitself, or it can be the appropriate number of any of these in packagedform. The quantity of active ingredient in a unit dose of compositionmay be varied or adjusted from 5 mg. or less of 500 or more, accordingto the particular need and the activity of the active ingredient. Theinvention also includes the compounds in the absence or carrier wherethe compounds are in unit dosage form.

The following Examples illustrate the invention and the preparation ofstarting materials for preparing the compounds of the invention.

EXAMPLE 1 3 ,4 -Dihydrospiro[1 ,3-dioxolane-2,10

(2I-I,lOH)pyrimido (1,2-a)indole 2'-Oxospiro[l,3-dioxolane-2,2'-indoline]-l propionitrile (37 g; Netherlands PatentApplication No. 6,507,422; Chem. Abs. 1966, 65, 2228, was reduced at aninitial pressure of 1200 p.s.i. and final temperature of 100C in ethanol(200 ml.) half saturated with ammonia, in the presence of Raney Nickel(6 g.) or 3 hours. After cooling, the catalyst was filtered off and thesolvent removed under reduced pressure to leave a viscous oil. The oilwas dissolved in xylene (200 ml.) and heated under reflux with stirringfor 26 hours in an apparatus fitted with a water separator. The xylenewas removed under reduced pressure, the dark oil dissolved in hot ethylacetate and treated with decolourising charcoal. The product, 25.9 g. ofcolourless needles, had m.p. 1l4-l15C. [Found: C, 68.0; I-I,5.9; N,12.2.G l-1 N requires C, 67.8; H, 6.1 N, 12.2%).

EXAMPLE 2 3,4-Dihydropyrimido[ l ,2-a]indoll O[2H]-one 3, 4-Dihydrospiro[1,3-dioxolane-2,10'(2I-I,1OH) pyrimido (1,2-a)indo1e] (12.2 g.) wassuspended in water (50 ml.) and concentrated hydrochloric acid (50 ml.)added with stirring. The mixture was heated at C for 5 hours. Themixture was evaporated to a red oil under reduced pressure, dissolved inabsolute ethanol ml.) and evaporated to 50 ml. On cooling, the productseparated as crimson needles (1.9 g.), m.p. 215-225C (decomp). (Found:C,59.0; H,5.0; N,l2.3, C l-l N O. l-lCl requires C,59.3; H,5.0;N,l2.6%).

EXAMPLE 3 3 ,4Dihydropyrimido[1,2-a]indol-l0[2H]-one Finely powdered 3,4'-dihydrospiro [1,3-dioxolane- 2,l0'(2H,10l-I)pyrimido(l,2-a)indole](l0g.) was added portionwise to stirring concentratedsulphuric acid 50 ml.) which was maintained at 25C by icebath cooling.On completion of the addition the mixture was stirred at roomtemperature overnight, poured onto ice and neutralised with concentratedaqueous ammonia solution, keeping the temperature below 30C. The mixturewas extracted with chloroform and dried over anhydrous magnesiumsulphate. After evaporation, the product was crystallised frombenzene/light petroleum (b.p. 6080C.) affording 7.3 g. of stout crimsonneedles, m.p. l21122C. (Found: C, 71.0; H, 5.4; N, 14.7. C,,H,,,N,0requires C, 70.95; H, 5.4; N, 15.05%).

EXAMPLE 4 2,3,4,lO-Tetrahydro-lO-phenylpyrimido[ l,2-a]indol 10-01Finely powdered 3,4-dihydropyrimido [l,2-a]indol- 10[2H]-onehydrochloride (3.82 g.) was added portionwise the phenyl magnesiumbromide [from magnesium (12.9 g.) and bromobenzene (8.2 g)] in ether(100 ml.). On completion, the reaction mixture was heated under refluxovernight, cooled and poured onto a mixture of ice and ammonium chloride(10 g.). The yellow solid which was deposited was filtered off andwashed with water and ether affording 3.67 g. of off white powder, m.p.2467C. (decomp).

The base could be recrystallised from ethanol as colourless rhombs, m.p.247-8C. (Found: C, 77.6; H, 6.2; N, 10.5. C H N O requires C, 77.3; H,6.1; N, 10.6%).

The hydrochloride of the base could be obtained by dissolving in hotabsolute ethanol and adding a solution of hydrogen chloride gas in dryether. The product, colourless needles, had m.p. 264-70C (decomp).(Found: C, 68.2; H, 5.7; N, 9.2. C H N O. l-lCl requires C, 67.85; H,5.7; N, 9.3%).

EXAMPLE 5 2,3,4, 1 O-Tetrahydro- 1 0-phenylpyrimido[ l,2-a]indol- Phenyllithium (0.05 mole.) in ether was added dropwise to a stirred suspensionof the pyrimido [1,2- a]indol-l0[2H]-one hydrochloride of Example 2(2.2g) in dry ether (IL) under a stream of nitrogen. The colourlesssolution formed was left at room temperature overnight and decomposed bythe addition of water (35 ml.) and 2N hydrochloric acid (15 ml.). Thesolid formed was filtered off, washed with water and dried affording thetitle compound (1.57 g.) m.p. 220225C. Recrystallisation from ethanolraised the m.p. to 246" 7C.

EXAMPLE 6.

2,3,4, 1 O-Tetrahydrol -phenylpyrimido{ l ,2-a]indollO-ol.

3,4-Dihydropyrimido] l ,2-alindol-l0-one (5.58 g.) in drytetrahydrofuran was added dropwise with stirring to phenyl magnesiumbromide (0.05 mole.) in dry ether (200 ml.). The reaction mixture washeated under reflux with stirring for 3 hours. The reaction mixture wasdecomposed by pouring onto a mixture of ice and ammonium chlorideaffording 6.38 g. pink powder, m.p. 230-5C (decomp). Recrystallisationfrom ethanol raised the m.p. to 246-8C (decomp).

EXAMPLE 7 lO-(p-Chlorophenyl)-2,3,4, 10tetrahydro-pyrimido[1,2-a]indol-l0-ol Finely powdered3,4-dihydropyrimido[1,2-a]-indoll0[2H]-one hydrochloride (6.5 g. 0.03mole.) was reacted with p-chlorophenyl magnesium bromide (0.2 mole.) indry ether (700 ml.) as described in Example 4. Work up with ice andammonium chloride afforded the base m.p. l85l9lC (demomp). (Found: C,68.4; H, 5.3; N, 9.4. C H N C10 requires C, 68.1; H, 5.1; N, 9.4%).

A total of 2.6 g. of the hydrochloride was obtained by dissolving inethanol and treating with a solution of hydrogen chloride in dry ether,m.p. 275279C (decomp). (Found: C, 60.2; H, 5.3; N, 7.6; Cl, 9.9. C H NCl0. HCl.'/2 C H OH requires C, 60.4; H, 5.35; N, 7.8; CI, 10.1%).

EXAMPLE 8 2,3,4, 1 O-Tetrahydro- 1 O-(o-tolyl )pyrimido[ 1,2-a]indol-'3,4-Dihydropyrimido[ 1 ,2-a]indoll 0[2H ]-one hydrochloride (6.66 g.;0.03 mole.) was reacted with otolyl magnesiumbromide (0.1 mole.) inether (1L) as described in Example 4. Work up afforded the base (4.1g.), m.p. 205-207C (decomp). (Found: C, 77.5; H, 6.7; N, 9.9.C H N Orequires C, 77.7; H, 6.5; N, 10.1%).

Treatment of the base in isopropanol with dry hydrogen chloride in etherafforded the hydrochloride as colourless fine needles (4.4 g.), m.p.300302C (decomp). (Found: C, 68.7; H, 6.25; N, 8.8. C H N O. HCl.requires C, 68.7; H, 6.1; N,8.9%).

EXAMPLE 9 2,3,4,lO-Tetrahydro-10-(p-toly)pyrimido[1,2-a]indollO-olFollowing the method of Example 4, 6.6 g. of 3,4- dihydropyrimido[l,2-a]indole- 1 0[2H]-one hydrochloride and p-tolyl magnesium bromide(0.15 ml.) in dry ether (1500 ml.) afforded the title compoundhydrochloride (1.28 g.) as colourless needles, m.p. 265267C (decomp).(Found: C. 68.9; H, 6.3; N, 8.9. C H N O. HCl requires C, 68.7; H, 6.1;N, 8.9%).

EXAMPLE 10 2,3,4, 10-Tetrahydro-l0-methylpyrimido[ l ,2-a]indoll0-olFollowing the method of Example 6, 3,4-dihydropyrimido[l,2-a]indol-lO[2H]-one (3.72 g.) was reacted with methylmagnesium iodide(0.06 mole.) in

ether (500 ml.). Attti 1 m; in 4 hours and leaving overnight th. actionmixture was poured onto ice and ammonium the ether layer separated andaqueous layer CabltClCd with chloroform. The chloroform extracts weredried over anhydrous magnesium sulphate and evaporated to a solid whichwas recrystallised from isopropanol affording 2.1 g. of fawn rhombs,m.p. l89-l9l C. (Found: C,7l.6; H,7.l; N,13.9. C H H O requires C,7l.3;H, 7.0; N,l3.85%). When this solid was dissolved in isopropanol andtreated with anhydrous hydrogen chloride in ether, 2.0 g. of thehydrochloride were obtained, m.p. 210-212C (decomp). (Found: C,60.8;H,6.3; N,l 1.7. C 2H N O. HCl requires C,60.4; H,6.3; N,l 1,7%).

EXAMPLE ll l0-Benzyl-2,3,4, l 0-tetrahydropyrimido[ l ,2- ]indol- 10- 0]Following the method of Example 6, the3,4-dihydropyrimido[l,2a]indole-l0[2H]-one (3.72 g.) was added dropwiseto a stirred solution of benzylmagnesium chloride (0.04 mole.) in dryether (300 ml.). The reaction was heated under reflux for 4 hours andleft overnight and decomposed by pouring onto ice and ammonium chlorideyielding the required base (4.3 g.), m.p. 22530C (decomp). Treatment ofan isopropanol solution with hydrogen chloride in dry ether afforded thehydrochloride as colourless fine needles, m.p. 241243C (decomp). (Found:C,68.9; H,6.2; N,9.l. CISHlBNZO. HCl requires C,68.7; H,6.1; N,8.9%).

EXAMPLE 12 1O-( m-Chlorophenyl )-2,3 ,4,10- tetrahydropyrimido[ l,2-a]indol-l0-ol Following the method of Example 6, the 3,4-dihydropyrimido-[l,2-a]indole-10[2H]-one (3.72 g.) was reacted withm-chlorophenylmagnesiumbromide (0.04 mole.) in dry ether (500 ml.). Thereaction mixture was heated under reflux 6 hours then left overnight.The mixture was poured onto ice and ammonium chloride and the productwas filtered off yielding 4.1 g. of a white powder, m.p. 193-5C(decomp). After converting to the hydrochloride, 4.79 g. of fineneedles, m.p. 27580C. (decomp) were obtained. (Found: C17H14N20.requires C,60.9; H,4.7; N,8.4%).

EXAMPLE l3 8 -Chloro-3 ',4 '-dihydrospiro 1,3-dioxolane-2, l 0'(2H,10H)pyrimido (l,2-a)indole] 3, 4'-Dihydrospiro[l,3-dioxolane-2,10(2H,l0H)pyrimido (1,2-a) indole] (2.3 g.) was heated under reflux with stirringin carbon tetrachloride (50 ml.) with N-chlorosuccinimide (1.43 g.) for16 hours. After cooling, the carbon tetrachloride was washed with 2N-sodium bicarbonate solution. The organic layer was then washed with 2Nhydrochloric acid. The acid extracts were basified with concentratedaqueous ammonia solution and the white solid extracted into ether. Afterdrying with anhydrous magnesium sulphate, the solvent was removed toleave an oil which was crystallised from light petroleum (b.p. 120C)containing a few drops of benzene. The product (0.73 g.) as

colourless needles had m.p. 1l2 1l4C. (Found: C,58.95; H,5.0;N,10.3.C,1-ll, C1l 1 O requires C,59.0; 114.95; N,10.6%).

EXAMPLE 14 3,4-Dihydrospiro[1,3-dioxolane-33-dimethyl- 2,10(2H,10H)pyrimido(1,2-a )indole] a. [satin (7.35 g.), ethyleneglycol (11.2m1.)and toluene-p-sulphonic acid (2 g.) in benzene (300 ml.) was heatedunder reflux in an apparatus fitted with a water separator for 5 hours,when water (2.1 ml.) was collected in the water separator and thereaction mixture had become colourless. The reaction mixture was cooled,washed with sodium bicarbonate solution and water. After drying overmagnesium sulphate the benzene was removed under reduced pressure andthe residue crystallised from methanol affording 9.9 g. of 2'-oxospiro[1,3-dioxolane 2,3'-indoline] as faintly pink needles, m.p.131-132C. (Found: C,62.72; H,4.8; N,7.2. C H N O requires C,62.8;1-1,4.8; N,7.2%).

b. t-Butylcyanide (42.0 g.) was heated at 60C with stirring in a mixtureof bromine (26 ml.) and carbon tetrachloride (IL) for 7 days,irradiating at the same time with a medium pressure ultra-violet lamp.The carbon tetrachloride was removed under reduced pressure and theresidual oil dissolved in dichloromethane and washed with sodiumbicarbonate then water. After drying over anhydrous magnesium sulphatethe solvent was removed and the product distilled affording 26 g. of3-bromo-2,2-dimethylpropionitrile as a colourless oil, b.p. 77-82C at 12mm. (Found: C,36.l; 1-1,4.8; N,7.4. C H BrN requires C,37.l; H,5.0;N,8.65%).

c. 2-Oxospiro [1,3-dioxolane-2,3-indo1ine], (3.8 g.) was addedportionwise to a stirred suspension of sodium amide (0.84 g.) in dryhexamethylphosphoric triamide (30 ml.) under a stream of nitrogen. Thereaction mixture was heated to 40C for 2 hours, cooled to 10C and3-bromo-2,2-dimethy1propionitrile (3.24 g.) added in one portion. Thereaction mixture was stirred at room temperature for 2 days. Thereaction mixture was poured into water and extracted with benzene. Thebenzene extracts were washed with dilute hydrochloride acid, dried overanhydrous magnesium sulphate and evaporated to a dark oil.Crystallisation from absolute ethanol afforded 3.05 g. of2'-oxospiro[1,3- dioxolane-2,3 -indoline]-1-[2,2-dimethylpropionitrile]as colourless rhombs, m.p. l 12113C. (Found: C,66.5; H,6.2; N,10.3. C1-1 N O requires C,66.2; H,5.9; N,10.3%).

d. The product of Example 14(c) (2.7 g.) was reduced in ethanolicammonia in the presence of Raney Nickel as described for Example 1.After work up, the product was heated under reflux with toluene for 24hours. Removal of the toluene and recrystallisation from benzeneafforded 1.23 g. of the title compound as colourless rhombs, m.p.109110C. (Found: C,70.0; H,7.2; N,1 1.1. C H N O requires C,69.7; H,7.0;N,10.85%).

EXAMPLE 1S 8-Chloro-2,3,4,10-tetrahydropyrimido[1,2-a]indol- 10[2H]-one8 -Chloro-3 ,4-dihydro-spiro[1,3-dioxolane- 2,10'(2H,10H)pyrimido(1,2-a)indole] (8.0 g.) was finely powered and added toconcentrated sulphuric acid (50 ml.) as described in Example 3.Following the method of that example, work up and recrystallisation frombenzene afforded red plates (5.8 g.), m.p. 163165C (decomp). Found:C,60.2; H,3.9; N,12.8. C H CIN O requires C,59.9; H,4.1; N,l2.7%.

EXAMPLE 16 8-Ch1oro-2,3,4,IO-tetrahydro-10-phenylpyrimido[ 1 ,2-a]indo1-10-ol Following the method of Example 6,8-Chloro-2,3,4,l0-tetrahydropyrimido[1,2a] indol-lO-one in tetrahydrofuran ml.)was added to a solution of phenylmagnesium bromide (0.026 mole.) inether (50 ml.). Mixture was heated under reflux with stirring for 5hours and after leaving overnight poured onto a mixture of ice andammonium chloride. The solid formed was filtered off, and washed withwater and ether to give 2.74 g. of a fawn powder, m.p. 240250C(decomp.). (Found: C,67.6; H,5.3; N,8.9.C H ClN O requires C,68.9;H,5.6; N,9.4%).

The powder was suspended in hot absolute ethanol and treated with asolution of dry hydrogen chloride gas in dry ether to give 1.89 g. offine needles, m.p. 279282C (decomp.). (Found: C,61.25; H48; N,8.5. C HClN O1-1C1 requires C,60.9; H,4.8; N,8.l%).

EXAMPLE 17 8-Chlorol0-(m-chloropheny1)-2,3 ,4,10-tetrahydro pyrimido[ l,2-a]indo1-10-ol Following the method of Example 6, 8-ch1oro-2,3,410-tetrahydropyrimido[1,2-a]indol-l0-one (2.8 g.) in dry tetrahydrofuran(60 ml.) was added to m-chlorophenylmagnesium bromide (0.03 mole.) inether (60 ml.). Reaction mixture heated under reflux for 4 hours. Afterleaving overnight, the reaction mixture was poured onto ice and ammoniumchloride. Organic layer separated and aqueous layer extracted withmethylene dichloride. Organic layer extracted with 2N- hydrochloricacid, acid layer basified, extracted into methylene dichloride; afterdrying over magnesium sulphate, solvent removed and residue dissolved inabsolute ethanol and treated with a solution of hydrogen chloride in dryether. Pale pink rhombs (1.61 g.), m.p. 279C (decomp.) were obtained.(Found: C,54.8; H,4.l5; N,7.3. C l-1 Cl N O. l-lCl requires C,55.2;1-1,4.1;N,7.6%).

EXAMPLE 18 10-(m-Anisy1)-2,3,4,l0-tetrahydropyrimido[ 1,2- a]indol-10-o1Following the method of Example 6, 2,3,4,l0-tetrahydropyrimido[l,2-a]indol-10-one (3.72 g.) in dry tetrahydrofuran(50 ml.) was added to m-anisylmagnesiumbromide (0.04 mole.) in ether (50ml.).

Heated under re+ux with stirring for 5 hours, left overnight then pouredonto ice and ammonium chloride. After acid-base extraction, 2.16 g. baseobtained, m.p. 255C (decomp). The solid was converted to itshydrochloride by solution in ethanol and addition of hydrogen chloridein dry ether to give 2.2 g. colourless rhombs, m.p. 260262C (decomp).(Found: C,65.5; H,6.0; N,8.5. G T-1 N 0 HCl requires C,65.3; 1-1,5.8;N,8.5%).

EXAMPLE l9 2,3,4,10-Tetrahydro-lO-(m-tolyl)pyrimido[1,2-

a]indol-l-ol Following the method of Example 6, 2,3,4,l0-tetrahydropyrimido[ l,2-a]indol--one in tetrahydrofuran (50 ml.) wasadded to m-tolylmagnesium bromide (0.05 mole.) in ether (200 ml.). Oncompletion of the addition the mixture was heated under reflux for 3hours. After leaving overnight, the reaction mixture was poured onto amixture of ice and ammonium chloride. The organic layer was separatedand the aqueous layer extracted with chloroform. After drying, thechloroform was removed to leave a red oil. Trituration with etherafforded a white solid. The solid was recrystallised from benzene-etherto give pale yellow rhombs (1.36 g.), m.p. l7980C. (Found: C,77.4;l-l,6.7; N,9.8. C H N O requires C,77.7; H,6.5; N,10.l%).

EXAMPLE 2O 2,3,4, 1 O-Tetrahydrol O-( 2-thienyl)pyrimido[1,2-alindole-lO-ol 2,3,4,lO-Tehydropyrimido[ 1,2-a]indol-l0-one(3.72 g.) in dry tetrahydrofuran (150 ml.) was added to 2- thienylmagnesium bromide (0.05 mole.) as described in Example 19. On thecompletion of the addition the reaction was stirred under reflux for 4hours. The reaction mixture was poured onto ice and ammonium chlorideand filtered to afford 4.38 g. ofa grey powder. The powder was suspendedin absolute ethanol, and treated with a solution of hydrogen chloride indry ether, the mixture was boiled and then treated with charcoal andfiltered. On dilution with ether the title compound was obtained ascolourless needles (3.68 g.), m.p, 226-228C (decomp.). (Found: C,58.6;H,5.0; N,9.9. C H 4N2OS. HCl requires C,58.7; H,4.9; N,9.1%).

EXAMPLE 2] l0-( m-Fluorophenyl)-2,3 ,4, l 0- tetrahydropyrimido[l,2-a]indol-10-ol 3 ,4-Dihydropyrimido[ l,2-a]indoll0[2H]-one (3.72g) indry tetrahydrofuran (100 ml.) was added dropwise to a stirred solutionof m-fluorophenyl magnesium bromide (0.05 mole) in dry ether. Thereaction mixture was stirred under reflux for 4 hours, cooled anddecomposed by pouring onto a mixture of ice and ammonium chloride. Theorganic layer was separated and the aqueous layer extracted withchloroform. Combined organic extracts were washed with water and driedover anhydrous magnesium sulphate. After removal of the solvent, theresidue was triturated with ether affording 3.3g. of fawn solid. Thesolid was suspended in boiling absolute ethanol, a solution of hydrogenchloride gas in dry ether added and the resulting solution treated withcharcoal and filtered. On cooling the filtrate the title compound as itshydrochloride crystallised as needles (3.3g), m.p. 28090C (decomp.)(Found: c,64.0; H,5.1;N,8.9.C H FN O.HCI requires C,64.05; H,5.l;N,8.9%)

EXAMPLE 22 10-(l-Naphthyl)-2,3,4,lO-tetrahydropyrimido[1,2-a)indol-10-ol Following the method of the previous example 3,4-dihydropryimido[1,2-a]indol-l0(2H)-one (2.86g.) in dry tetrahydrofuran(100ml.) was added to l-naphthylmagnesium bromide (0.05 mole). After workup and removal of the solvent the base was obtained as an oil which wasconverted to the hydrochloride in the usual way. The product (3.8g) hadm.p. 270274C- (decomp.) (Found: C,7I.O, H,5.5; N,7.7. C ,H N O.HCl.l/4HO requires C,71.25; H,5.5; N,7.9%)

EXAMPLE 23 lO-(o-Chlorophenyl )-2,3 ,4, l 0- tetrahydropyrimido[ 1,2-a]indol-lO-ol EXAMPLE 24.

10-(m-Trifluoromethylphenyl )-2,3 ,4, l 0- tetrahydropyrimido[ l,2-a]indol-10-ol.

Following the method of Example 21,3,4-dihydropyrimido[1,2-a]indol-lO[2H]-one (2.7g) was added to asolution of m-trifluoromethylphenylmagnesium bromide (0.05 mole). Afterpouring onto ice and ammonium chloride solution, the precipitated basewas removed and the organic layer worked up and evaporated to give afurther quantity of base. The base was converted to the hydrochloride inthe usual way yielding 3.95g. of the title compound as thehydrochloride, m.p. 29l2C(decomp.). (Found: C,58.6; H,3,3;

N,7.5. C H F N OHCl requires C,58.6; H,4.4; N,7.6%).

EXAMPLE 25 lO-(3,4-Dichlorophenyl)2,3,4,10- tetrahydropyrimido[1,2-alindol- 1 0-01.

Following Example 21, 3,4-dihydropyrimido[ l ,2- a]indol-lO[2h]-one(2.7g.) was reacted with 3,4-dichlorphenylmagnesium bromide (0.05 mole).After work up, the organic layer was separated and the aqueous layerextracted with chloroform. The combined organic extracts were treatedwith 2N hydrochloric acid and the precipitated hydrochloride filteredand dried. Recrystallisation from methanol/ether afforded 3.4g. ofcolourless needles, mp. 28790C (decomp). (Found: C,54.9; H,4.l; N,7.5. C-,H Cl N O.HCl requires C,55.2; H,4.1; N,7.6%).

EXAMPLE 26 l0-(p-Fluorophenyl)-2,3,4,10- pyrimidq 1 ,2-a]indol- 10-01.

Following the method of Example 21,3,4-dihydropyrimido[l,2-a]indol-lO[2H]-one (2.5g), was reacted withp-fluorophenylmagnesium bromide (0.05 mole). The hydrochloride wasformed in the usual way, yielding 2.4g. of cream coloured needles, mp.270272C.(Found: C, 63.9; H,4.9; N, 8.6. C H FN OHCI requires C,64.0; H,5.1; N,8.8%).

EXAMPLE 27 2,3 ,4,10-Tetrahydro10-(o-trifluoromethylphenyl)- pyrimidol,2-a]indol-l-ol.

Following the method of Example 21, 3,4-dihydropyrimido[l,2-a]indol-l0[2l-l]-one (2.79g.) was reacted witho-trifluoromethylphenylmagnesium bromide (0.05 mole). The hydrochloridewas obtained as fine needles (3.72 g.), m.p. 2557C(decomp.). (Found:C,58.4; H,4.9; N,7.3. c,,,H,,F,N o.Hc1. /2 C H OH requires C,58.2;H,4.9; N,7.15%).

EXAMPLE 28 lO-(2,3-Dichlorophenyl)-2,3,4,10- tetrahydropyrimido[1,2-a]indol--ol.

Following the method of Example 21,3,4-dihydropyrimido[1,2-a]indol-10[2H]-one (1.86g.) was reacted with2,3-dichlorophenylmagnesium bromide (0.025 mole). After work up, thebase was obtained as an oil which afforded 1.93g. of the hydrochloride,m.p. 292-4C(decomp.). (Found: C,52.7; l-l,4.1; N,7.3.

C l-l Cl N OHClH o requires C,52.7; l-l,4.4; N,7.2%).

EXAMPLE 29 3,4-Dihydro-3,3-dimethylpyrimido[ 1,2-a]indoll0[2H]-one.

3 ,4'-Dihydrospiro[ 1,3-dioxolane-3 ,3'-dimethyl-2,l0'(2l-l,1OHl)pyrimido( l, 2-a)indole](8.5g.) was added portion-wiseto concentrated sulphuric acid (100 ml.) keeping the temperature below30C, and controlling the rate of addition so that all the ketal haddissolved before the next portion was added. After leaving stirring atroom temperature overnight, the mixture was poured onto ice andneutralised with concentrated aqueous ammonia keeping the temperaturebelow 30C. The red oil was extracted into methylene dichloride, driedover anhydrous magnesium sulphate, evaporated to a red foam whichafforded 5.98g. of scarlet rhombs, m.p.125-126C from benzene-lightpetroleum (b.p. 40-60C). (Found: C,73.3; H,6.7; N,13.0.

'C H N O requires C,72.9; H,6.6; N,13.1%).

EXAMPLE 3O 10-( m-Chlorophenyl )-2,3 ,4,10-tetrahydro-3 ,3-dimethylpyrimido[1,2-a]indol-10-ol.

EXAMPLE 31 2,3,4, 1 O-Tetrahydro- 1 O-phenyl-3 ,3-dimethylpyrimido[1,2-a]indol-lO-ol.

Following the method of Example 21 3,4-dihydro-3,3-dimethylpyrimido[1,2-a]indol-10[2H]-one (3g), was reacted withphenyl magnesium bromide (0.05 mole). After work up, 2.4g. of thehydrochloride was obtained m.p. 260-261C(decomp.). (Found: (1,690;

H,6.75, N,8.3. C 9H20N O. HCl requires C,69.4; H,6.4; N,8.5%).

EXAMPLE 32 3.4-Dihydro-8-methoxypyrimido[ l ,2-a]indol- 10( 2l-l)-one.

a. 5-Methoxy-2,3-dioxoindoline- 1 -propionitrile 5-Methoxyisatin(20.28g; M.Akahoshi, .LPharm. Soc. Japan, 1951, 71, 710-711; Chem.Abstracts, 1952, 46, 2047) and 40% aqueous solution of benzyltrimethylammonium hydroxide (5ml.) was heated to reflux in absoluteethanol (500ml.) and acrylonitrile (19ml., added dropwise. The mixturewas heated under reflux for 30 minutes, cooled and the purple crystalsfiltered off to afford 17.39g. of the title compound. The product wasrecrystallised from aqueous dimethylformamide for characterisation, m.p.182-185C. (Found: C,62.5; H,4.5; N,12.2. C t-1 N 0 requires C,62.5;l-l,4,4; N,12.2%).

b. 2 -0xospiro [1 ,3-diox0lane-2 ,3 -(5- methoxyindoine)]-l'-propionitrile.

Ethane-1,2-diol 12 m1. 5-methoxy-2,3- dioxoindoline- 1 -propionitrile16.4g.), benzene (500ml.) and toluene-p-sulphonic acid (0.5g.) wereheated together under reflux in an apparatus fitted with a waterseparator. After 12 hours, the theoretical quantity of water hadseparated. The mixture was washed with water then sodium bicarbonatesolution and the organic phase dried over anhydrous magnesium sulphate.After removal of the solvent and recrystallisation from propan-2-ol13.6g. of the product was obtained, m.p. ll0-111C. (Found: C,61.5;l-l,5.2; N,10.3. C I-1 N 0 requires C,61.2; H,5.1; 10.2%).

c. 3',4'-Dihydrospiro[1,3-dioxolane-2,10'(2l-l,10H)- 8-methoxypyrimido[1,2-a]indole] The product of part (b) 13g.) was reduced at an initialpressure of 1,100 psi. of hydrogen and a temperature of 40C in absoluteethanol (400 ml.) half saturated with ammonia in the presence of W7Raney Nickel (2.0g.) for a period of 4 hours. The reaction mixture wascooled, the catalyst filtered off and the ethanol removed under reducedpressure. The product was dissolved in toluene and heated under refluxwith phosphorus oxychloride (10 drops) for 12 hours. The insolublematerial was filtered off and the toluene removed under reduced pressureto leave an oil which spontaneously crystallised. The oil was convertedto the hydrochloride and recrystallised from propan-2-ol affording5.65g. of product which decomposed at 300-360C. (Found: C,56.53;l-1,5.7; N,9.15. C I-1 N 0 HCl requires C,56.65; l1,5.8; N,9.4%).

d. The product of part (c) (4.6g.) was added the stirring toconcentrated sulphuric acid (50ml.) keeping the temperature below 20C.The mixture was stirred for 30 minutes then poured onto ice. Afterneutralisation with ammonia, the purple product was extracted intochloroform, dried over magnesium sulphate and, after removal of thesolvent, recrystallised from benzene affording 2.7g. of purple rhombs,m.p.

-151C. (Found: C,66.9; l-1,5.7; N,12.7.

C12H 2N2O2 requires C,66.7; l-l,5.6; N,13.0%)

EXAMPLE 33 10-( m-Chlorophenyl)-8-methoxy-2,3 ,4,10- tetrahydropyrimido[l,2-a]indol-10-ol.

Following the method of example 21, 3,4-dihydro-8-methoxypyrimido[1,2-a]indol-l(2H,-one, (l.45g.), was reacted withm-chlorophenylmagnesium bromide (0.025mole). Work up afforded 1.36g. ofthe hydrochloride, m.p. 282283C: (decomp.). (Found: C,59.2; H,5.l; N,7.6C H, ClN O .HC1 requires C,59.1; H,5.0; N,7.6%).

EXAMPLE 34 2,3,4,10-Tetrahydro-8-methoxy-l0-phenylpyrimidol1,2-a]indol-l0-ol.

Following the method of Example 21, 3,4-dihydro-8-methoxypyrimidol1,2-a]indol-10(2H)-one (1.45g.) was reacted withphenylmagnesium bromide (0,025mole.). Work up afforded 1.29g. of thehydrochloride, m.p. 2858C. (decomp.). (Found: C,64.l; H58; N,8.4. C l-lN O HCl requires C,65.25; H58; N,8.45%).

EXAMPLE 35 2,3 ,4, l O-Tetrahydro-8nitropyrimido[ 1,2-a] indol- 10(2H)one EXAMPLE 36 lO-(o-Fluorophenyl)-2,3,4,10- tetrahydropyrimido[ l,2-a]indol-10-ol.

3,4-Dihydropyrimido[ l,2-a]indol-10(2H)-one (1.86g.) in drytetrahydrofuran (80ml.) was added to a solution of o-fluorophenyllithium(0.02 mole.) in ether (50ml.) at 60C. On completion of the addition thecolourless reaction mixture was stirred at 60C for 2 hours then pouredonto ice and ammonium chloride solution. When the mixture had warmed toroom temperature, the base was filtered off. The hydrochloride wasformed in the usual way yielding 2.8g., m.p. 269-70C (decomp.). (Found:C,63.6; l-I,5.0; N,8.6. C H FN O. HCl requires C,64.05; H,5.l; N,8.6%).

EXAMPLE 37 1 O-Tetrahydrol O-( 2 ,6- dimethylphenynpyrimidol 1-a]indo1-l() 1 3,4-Dihydropyrimido[ l ,2-a]indollO(21-1)-one (1.86g), intetrahydrofuran was added to 2,6- dimethylphenyl magnesium bromide (0.02mole.) prepared by the entrainment method. The reaction mixture wasworked up as described in example 1 and the hydrochloride obtained ascolourless needles (1.35g.), m.p. 2746C. (decomp.). (Found: C,69.5;H,6.55; N,8.4. C H N O. HCl requires C,69.0; H,6.4; N,8.5%).

3,4-Dihydropyrimidol l ,Z-nlindoL 1 2H )-one (7.4g.) in tetrahydrofuranwas reacted with cthynylmagnesium bromide (0.15 mole.) as described inExample 21. After work up, 5.8g. of the base was obtained, m.p. 2246C(decomp). The hydrochloride had m.p. 210215C(decomp.). (Found: C,62.5;H,5.4; N,1 1.0. C H N O. HCl requires C,62.8; H,5.3; N,11.3%).

EXAMPLE 39 10-( m-Chlorophenyl )-2,3 ,4, lO-tetrahydropyrimido[1,2-a]indol-l0-ol acetate.

2,3,4,lO-Tetrahydro-lO-(m-chlorophenyl)pyrimido [1,2-a]indol-10-ol (3g)was dissolved in acetic anhydride ml.) and left at room temperature for48 hours. The acetic anhydride was removed under reduced pressure andthe residue re-evaporated with tol uene (50 ml.). The residue wasdissolved in the minimum quantity of ethanol and treated with a solutionof hydrogen chloride in dry ether. The product hydrochloride wasobtained as colourless rhombs (324g), m.p. 2l3216C (decomp.). (Found:C,60.4; H,4.8; N,7.3. C H ClN O HCl requires C,60.5; 11,4.8; N,7.4%).

EXAMPLE 4O (+)-10-(m-Chlorophenyl-2,3,4,lO- tetrahydropyrimido[ 1,2-a:indol-10-ol.

2,3 ,4,] O-Tetrahydro-10-(m-chlorophenyl)pyrimido [1,2-a]indol-lO-ol(6.6g.) was dissolved in hot absolute ethanol and L(+) (natural)tartaric acid (3.3g.) added. The mixture was heated until solution wascomplete. Crystallisation afforded a total of 2.23g. of the L(+)tartarate salt. Recrystallisation 3 times and evaporation of the motherliquors afforded a total of 2. lg.[oz]D 709] (c 1 in methanol), m.p.118C (decomp.). (Found: C,55.7; H, 5.0; N,6.2. C 7H 5ClNzO.

(CHOH.COOH) requires C,56.2; H,4.7; N,6.2%)

EXAMPLE 41 1 0-m-Chlorophenyl-2,3 ,4,10-Tetrahydropyrimido[ l,2-a]indol- 1 0-01.

The mother liquors from example 40 consisting the ()isomer, wereevaporated to dryness and converted to the base (3.84g.) The base wasdissolved in hot ethanol and treated with D() (unnatural) tartaric acid.After working up as in Example 40, 2.0g of the laevo base as the D()tartarate salt was obtained. [a]D .,71.4 (c l in methanol), m.p. 118C(decomp).

EXAMPLE 42 2,3 ,4, l 0-TetrahydrolO-( 2-pyridyl )pyrimido[ 1,2- a]indol-10-01.

3,4-Dihydropyrimido [l,2-a]indol-10-(2H) one (4.0g.) in drytetrahydrofuran (10ml) was added to a solution of 2-pyridy1 lithium(0.04 mole) at 40C. The reaction mixture was allowed to warm up to roomtemperature over 2 hr. then decomposed by adding to ice and ammoniumchloride. The organic layer was separated and the aqueous layerextracted with chloroform. After drying over anhydrous magnesiumsulphate the solvent was removed and the base obtained as 2.73g. of afawn powder. The hydrochloride was formed in the usual way, affording3.0g m.p. 268-70C. (Found: C,56.0; H,5.2; N,l2.4. C, H, N O.2HCl.l/4 H Orequires C,56.l; H,5.0; N,12.3%).

EXAMPLE 43 l-(m-Chlorophenyl )-2,3,4, 1 O-tetrahydrolO-hydroxy1-methylpyrimido[ 1,2-a]indolinium iodide.

10-(m-Chlorophenyl)-2,3,4,IO-tetrahydropyrimido [l,2-a]indoll0-ol(2.94g.) was dissolved in hot 2- propanol (SOmL) and methyl iodide(2ml.) added. Heated under reflux for 30 minutes. On cooling theindolinium iodide separated, 4.03g. decomposed without melting at250254C.

(Found: C,49.3; l-l,4.3; N,6.6. C H CIIN O requires C,49.l; H,4.l;N,6.3%).

EXAMPLE 44l0-(m-Chlorophenyl)-1,2,3,4,10,10a-hexahydro-lmethylpyrimido[1,2-a]indol-lO-ol.

EXAMPLE 45 l,2,3,4,l0,10a-Hexahydro-10-phenylpyrimido[1,2-a]indol-l0-ol.

1,2,3 ,4-Tetrahydro- 1 0-phenylpyrimido[ I ,2-a]indollO-ol (1.9g.) wasadded as a slurry in dry tetrahydrofuran to a suspension of lithiumaluminium hydride (O.6g.) in dry tetrahydrofuran (20ml) The reactionmixture was stirred under reflux for 3 hours, cooled and decomposed withwater. After separation of the organic material and removal of solvent ayellow oil was obtained which solidified on trituration with ethergiving 1.0g., mp. 147C. (Found: C,76.25; H,7.0; N,10.4. C H N O requiresC,76.7; H,6.8; N,10.5%).

The fumarate was obtained from 2-propanol, mp. 157C. (Found: C,70.3;H,6.2; N,8.4. [C, H, N O] C ll-I O: requires C,70.35; H,6.2; N,8.6%).

EXAMPLE 46 l,2,3,4,10,10a-Hexahydrospiro[ l,3-dioxolane-2,10- [3',3-dimethyl]pyrimido[1,2-a]indol].

2-Oxospiro[ 1,3 dioxolane-2,3indoline]-l -[2,2-dimethylpropionitrile](17.5g) was reduced at an initial pressure of1,500 psi. and 100C for 5 hours in ethano] (200ml) half saturated withammonia in the presence of Raney nickel W.7. (8g). The catalyst wasremoved and the ethanol removed under reduced pressure. The residual oilwas crystallised from benzene, affording 12.09 g., m.p. 9396C. (Found:C,69.7; l-l,7.7; N,10.8. C, H N O requires C,69.2; H,7.7; N,10.8%).

EXAMPLE 47 Capsules l0-( m-Chlorophenyl )-2,3,4, 1 O-tetrahydropyrimidol1,2-alindoH0-ol 50 mg. Lactose 108 mg. Tale 2 mg.

the methiodides thereof and the acid addition salts thereof withpharmaceutically acceptable acids, in which R represents hydroxyl,acetoxy, propionoxy or butyryloxy, R represents a member of the groupconsisting of phenyl, lower alkyl, lower alkynyl, benzyl, naphthyl,thienyl, pyridyl, monohalophenyl, dihalophenyl, lower alkyl phenyl,di(lower alkyl)phenyl, lower alkoxyphenyl, and trifluoromethylphenyl, Rand R (which may be the same or different) represent hydrogen, halogenor lower alkoxy, R and R (which may be the same or different) representhydrogen or lower alkyl, the dotted line represents an optional bond inthe position indicated, and R, which is present only when the optionalbond represented by the dotted line is absent, represents hydrogen orlower alkyl.

2. An indole derivative according to claim 1 in which the dotted linerepresents a bond in the position indicated, R R, R and R representhydrogen atoms, R represents hydroxyl and R represents a member of thegroup consisting of phenyl, monohalophenyl, dihalophenyl,lower-alkylphenyl, di(lower alkyl) phenyl, lower alkoxyphenyl andtrifluoromethylphenyl.

3. An indole derivative according to claim 11 which is2,3,4,10-tetrahydro-l0-phenylpyrimido[1,2-a]indol- 10-01.

4. An indole derivative according to claim 1 which is 1O-(m-chlorophenyl )-2,3 ,4, l O-tetrahydropyrimido- [1,2-a1indol-lO-ol.

5. An indole derivative according to claim 1 which is 10-(p-chlorophenyl)-2,3 ,4,10-tetrahydropyrimido[1,2-a]indol-lO-ol.

6. An indole derivative according to claim 11 which is 2,3,4, 1O-tetrahydro-10-( 2-thienyl )pyrimido[ l,2-a]- indol-lO-ol.

is 13A 'lciruhydrolU-phcny|-3,3- dimethylpyrimido[ l,2.-a ImdollO-ol.

11. An indole derivative :iccnrding to claim 1 which is(+)-lO-(m-chlorophenyl)-2.3,4,l0-tetrahydropyrimido[ l,2-a]indoll O-ol12. An indole derivative according to claim 1 which is()-10-(m-chlorphenyl)-2,3,4,IO-tetrahydropyrimido[1,2-a]indo]-lO-ol.

. UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO.3,891,644 g 1 of a DATED June 24,1975 iNvENTOR(S) Alan Chapman White Itis certified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below: i

Q In the Title, "l,2,3,4,10A-HEXAHYDROPYRIMIDOL" should read 1,2,3,4,10,

IDA-HEXAHYDROPYRIMIDO In the Assignee, "(Ltd.)," should read M LimitedIn the Abstract, line 12, "Hexahydropyrimido" should read hexahydro- Opyrimido Column 1, line 28, "alkynl" should read alkyny1-;

Column 1, line 30, "alkly" should read alkyl 0 Column 2, line 32, "-10"should read -10-o1 Column 2, line 39, "2,3,5,10-" should read 2,3,4,l0-

Column 2, line 43, "3,3dimethy1pyrimido" should read3,3-dimethylpyrimido 6 6' Column 4, line 40, "R should read R Column 6,line 63, "Lift" should read Life Column 9, line 46, "indole" should readindole] UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT N0.3,891,644

DA E J1me 24,1975 Page 2 of 4 O INVENTOR(S) Alan Chapman White It iscertified that error appears in the above-identified patent and thatsaid Letters Patent are hereby corrected as shown below: 7

Column 9, line 49, "2228," should read 2228) Column 9, line 53, "or"should read for Column 10, line 34, "the" should read to 1' II o TColumn 12, l1ne 9, C H H O should read C H N O Column 13, line 44,"ride" should read ric Column 14, line 10, "Example 6,8-Chloro" shouldread Example 6, 8- Chloro- Column 14, line 59, "re ux" should readreflux Column 15, line 59, "c,64.0;" should read C,64.0;

Column 16, line 47, "l0[2h ]-one" should read l0[2H] on k Column 18,line l3, "(19 ml.," should read (19 ml.)

Column 18, line 22, "methoxyindoinefl l'-propionitrile should readmethoxyindoline)] l'-pr opionitrile Column 18, line 53, "added thestir-" should read added with stir- Column 19, line 1, "(2H," shouldread (2H) UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENTNO. 3,891,644 Page '3 -f 4 DATED June 24,1975 0 INVENTOR(S) I AlanChapman White It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

. Column 20, the f irst three lines should read v Example 3810-Ethynyl-2,3,4,10-tetrahydropyrimido[l,2-a] indol-lO-ol Column 20,line 33, "[1,2-az" should read [1,2-a]

Column 20, line 39, "tartarate" should read tartrate Column 20, line 53,"tartarate" should read tartrate Column 21, line 34, "C 19Cln O shouldread C H ClN 0 Claim 1, line 1, "consisted" should read consisting Claim1, line 3 4 Q should read R R R UNITED STATES PATENT OFFICE CERTIFICATEOF CORRECTION PATENT NO. 2 3,891,644 Page 4 of DATED June 24,1975

INVENTOR(S) 1 Alan Chapman White It is certified that error appears inthe above-identified patent and that said Letters Patent are herebycorrected as shown below:

Claim 10, line 2, "(3,4-dich1orpheny1)" should read (3,4-dich1oropheny1)and Claim 12, line 2, "(m-chlorphenyl)" should read (m-chlorophenyl)Signed and Scaled this T weary-ninth Day May 1979 [SEAL] Arrest:

DONALD w. BANNER RUTH c. MASON Arresting Oflicer Commissioner of Patentsand radenlarkls

1. A COMPOUND SELECTED FROM THE GROUP CONSISTED OF INDOLE DERIVATIVESHAVING THE FORMULA:
 2. An indole derivative according to claim 1 inwhich the dotted line represents a bond in the position indicated, R2,R3, R4 and R5 represent hydrogen atoms, R represents hydroxyl and R1represents a member of the group consisting of phenyl, monohalophenyl,dihalophenyl, lower-alkylphenyl, di(lower alkyl) phenyl, loweralkoxyphenyl and trifluoromethylphenyl.
 3. An indole derivativeaccording to claim 1 which is2,3,4,10-tetrahydro-10-phenylpyrimido(1,2-a)indol-10-ol.
 4. An indolederivative according to claim 1 which is10-(m-chlorophenyl)-2,3,4,10-tetrahydropyrimido-(1,2-A)indol-10-ol. 5.An indole derivative according to claim 1 which is10-(p-chlorophenyl)-2,3,4,10-tetrahydro-pyrimido(1,2-a)indol-10-ol. 6.An indole derivative according to claim 1 which is2,3,4,10-tetrahydro-10-(2-thienyl)pyrimido(1,2-a)-indol-10-ol.
 7. Anindole derivative according to claim 1 which is10-(m-fluorophenyl)-2,3,4,10-tetrahydropyrimido(1,2-a)indol-10-ol.
 8. Anindole derivative according to claim 1 which is10-(3,4-dichlorphenyl)-2,3,4,10-tetrahydropyrimido(1,2-a)indol-10-ol. 9.An indole derivative according to claim 1 which is10-(m-chlorophenyl)-2,3,4,10-tetrahydro-3,3-dimethylpyrimido(1,2-a)indol-10-ol.
 10. An indole derivative according to claim 1 which is2,3,4,10-tetrahydro-10-phenyl-3,3-dimethylpyrimido(1,2,-a)indol-10-ol.11. An indole derivative according to claim 1 which is(+)-10-(m-chlorophenyl)-2,3,4,10-tetrahydro-pyrimido(1,2-a)indol-10-ol.12. An indole derivative according to claim 1 which is(-)-10-(m-chlorphenyl)-2,3,4,10-tetrahydro-pyrimido(1,2-a)indol-10-ol.